title: Short-course rapamycin treatment preserves airway epithelium and protects against bronchiolitis obliterans.
abstract: BACKGROUND
  Damage to airway epithelium is closely related to the development of bronchiolitis obliterans (BO) in pulmonary transplantation. Rapamycin protects against BO development in a murine model, but its use in patients undergoing lung transplantation is limited by its side effects. We hypothesized that short-course rapamycin dosing could be used to prevent airway epithelium loss and protect against BO development in a murine model.
  
  
  METHODS
  A total alloantigenic mismatch, murine, heterotopic tracheal transplant model of BO was used. Animals were treated with either rapamycin or dimethyl sulfoxide (controls) according to one of three treatment regimens: (1) days 1 through 14 after transplantation, (2) days 3 through 7 after transplantation, or (3) days 14 through 28 after transplantation. Epithelial loss was assessed by use of hematoxylin and eosin stains 14 and 28 days after transplantation. Tracheal luminal obliteration was assessed at 28 days.
  
  
  RESULTS
  Early rapamycin treatment was protective against epithelial loss 14 days after transplantation in comparison with control animals (p < 0.001). Rapamycin treatment from days 1 to 14 was more effective at epithelial preservation (p = 0.002) and reducing luminal obliteration (p < 0.001) at 28 days than was rapamycin treatment from days 3 to 7. Late rapamycin treatment (days 14 to 28) allowed for recovery of the previously denuded epithelium at 28 days (92.5% epithelial loss to 35.6%) and a reduction in BO (p < 0.001).
  
  
  CONCLUSIONS
  Short-course rapamycin treatment protects against airway epithelium loss and subsequent development of BO in a murine model. Because of its immunosuppressive and antifibrotic effects, rapamycin may prove to be the ideal medication to prevent chronic rejection and BO in patients undergoing lung transplantation.
authors.affiliation: Department of Surgery, Division of Thoracic and Cardiovascular Surgery, University of Virginia Health System, Charlottesville, VA, USA.
authors.forename: Jacob R
authors.initials: JR
authors.lastname: Gillen
authors.affiliation: Department of Surgery, Division of Thoracic and Cardiovascular Surgery, University of Virginia Health System, Charlottesville, VA, USA.
authors.forename: Yunge
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Surgery, Division of Thoracic and Cardiovascular Surgery, University of Virginia Health System, Charlottesville, VA, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Harris
authors.affiliation: Department of Surgery, Division of Thoracic and Cardiovascular Surgery, University of Virginia Health System, Charlottesville, VA, USA.
authors.forename: Damien J
authors.initials: DJ
authors.lastname: LaPar
authors.affiliation: Department of Surgery, Division of Thoracic and Cardiovascular Surgery, University of Virginia Health System, Charlottesville, VA, USA.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Kron
authors.affiliation: Department of Surgery, Division of Thoracic and Cardiovascular Surgery, University of Virginia Health System, Charlottesville, VA, USA.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Lau
mesh_terms: D000818:Animals; D001989:Bronchiolitis Obliterans / Q000209:etiology* / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016040:Lung Transplantation / Q000009:adverse effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D020545:Respiratory Mucosa; D020123:Sirolimus / Q000008:administration & dosage*
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus
keywords: 12